This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-MH- 102 Schizophrenia Interactome. Schizophrenia is thought to be a complex neurodevelopmental disorder with many genetic factors contributing to its pathology, possibly in an interrelated or convergent manner. Two of the strongest susceptibility genes for Schizophrenia are neuregulin 1 (NRG1) and DISC1. Although they are broadly expressed in the developing brain and are thought to play important roles in neurodevelopmental processes, it remains unclear if these molecules are functionally related to each other and how this interaction affects cerebral cortical development. We hypothesize that changes in the functional interactions between these genetic factors and the resultant changes in the formation of neural circuitry in the cerebral cortex may lead to neurodevelopmental disorders such as schizophrenia. An understanding of the functional interactions between these important SZ susceptibility genetic factors in the developing cerebral cortex will be essential to delineate the pathophysiological processes that culminate in schizophrenia. To accomplish this, we will (1) determine the effects of NRG1 on DISC1 expression and the underlying signaling mechanisms in the developing cerebral cortex and (2) define the functional significance of NRG1-DISC1 interactions in the formation of cerebral cortex. This integrated analysis of how strong susceptibility genetic factors for schizophrenia interact during cortical development will help to decipher some of the key neurodevelopmental pathways whose disruption can lead to the development of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a complex neurodevelopmental disorder with many genetic factors contributing to its pathology in an interrelated or convergent manner. Two of the strongest susceptibility genes for Schizophrenia are neuregulin 1 (NRG1) and DISC1. Changes in the functional interactions between these genetic factors and the resultant changes in the formation of neural circuitry in the cerebral cortex may lead to schizophrenia. Therefore, we aim to define how susceptibility genetic factors for schizophrenia interact during cortical development. This will help to decipher the key neurodevelopmental pathways whose disruption can lead to the development of schizophrenia.